letermovir

le-TERM-oh-vir

Therapeutic Classification: antivirals

REMS

Prevention of cytomegalovirus (CMV) infection and disease in CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant.
Prevention of CMV disease in kidney transplant recipients at high risk (donor CMV seropositive/recipient CMV seronegative).

Prevents viral DNA processing and packaging by inhibiting the CMV DNA terminase complex.

Therapeutic effects:

Prevention of clinically significant CMV infection following transplant.

Absorption: 35% absorbed following oral administration (↑ when cyclosporine given); IV administration results in complete bioavailability.

Distribution: Widely distributed.

Protein Binding: 99%.

Metabolism/Excretion: Primarily metabolized in liver via UGT1A1/UGT1A3; 93% excreted in feces (70% as unchanged drug); <2% excreted in urine.

Half-Life: 12 hr.

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
IV	rapid	end of infusion	unknown
PO	unknown	0.75–2.25 hr	unknown

Contraindicated in:

Concurrent use of pimozide or ergot alkaloids;
Concurrent use of pitavastatin and simvastatin when administered with cyclosporine;
Severe hepatic impairment.

Use Cautiously in:

Renal impairment (CCr <50 mL/min; accumulation of IV vehicle may occur [closely monitor serum creatinine]);
OB: Safety not established in pregnancy;
Lactation: Safety not established in breastfeeding;
Pedi: Safety and effectiveness not established in children 12 yr (kidney transplantation) or 6 yr (allogeneic hematopoietic stem cell transplantation).

CV: peripheral edema, atrial fibrillation, tachycardia

GI: abdominal pain, diarrhea, nausea, vomiting

GU: ↑serum creatinine

Hemat: anemia, neutropenia, thrombocytopenia

Neuro: fatigue, headache

Resp: cough

Drug-drug:

May ↑ pimozide levels, which may ↑ risk of torsades de pointes; concurrent use contraindicated.
May ↑ ergotamine and dihydroergotamine levels, which may ↑ risk of ergotism; concurrent use contraindicated.
May significantly ↑ pitavastatin and simvastatin levels when concurrently administered with cyclosporine, which may ↑ risk of myopathy and rhabdomyolysis; concurrent use contraindicated.
May ↑ amiodarone levels and risk of toxicity; closely monitor amiodarone concentrations.
May ↓ warfarin levels and ↑ the risk for a thromboembolic event; closely monitor INR.
May ↓ phenytoin levels; concurrent use not recommended.
May ↑ glyburide, repaglinide, and pioglitazone levels; closely monitor blood glucose levels; when used concurrently with cyclosporine, avoid use with repaglinide.
May ↓ voriconazole levels and effectiveness.
Bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, nevirapine, phenobarbital, phenytoin, rifabutin, rifampin, and thioridazine may ↓ levels and effectiveness; concurrent use not recommended.
May ↑ atorvastatin levels and the risk of toxicity; do not exceed atorvastatin dose of 20 mg/day; when used concurrently with cyclosporine, avoid use with atorvastatin.
May ↑ pitavastatin and simvastatin levels and the risk of toxicity; concurrent use not recommended.
May ↑ fluvastatin, lovastatin, pravastatin, and rosuvastatin levels and the risk of toxicity; consider ↓ statin dose; when used concurrently with cyclosporine, avoid use with lovastatin.
Concurrent use with cyclosporine↑ both cyclosporine and letermovir levels; ↓ letermovir dose and closely monitor whole blood concentrations of cyclosporine.
May ↑ sirolimus and tacrolimus levels and the risk of toxicity; closely monitor whole blood concentrations of sirolimus and tacrolimus.
May ↓ omeprazole and pantoprazole levels and effectiveness.

Drug-Natural Products:

St. John's wort may ↓ levels and effectiveness; concurrent use not recommended.

IV therapy should only be used when patients are unable to take oral therapy.

Hematopoietic Stem Cell Transplant

IV PO (Adults and Children ≥12 yr and ≥30 kg): 480 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease. Concurrent use with cyclosporine: 240 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease.
PO (Children ≥12 yr and 15–<30 kg): Tablets or oral pellets: 240 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease. Concurrent use with cyclosporine: Oral pellets: 120 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease.
PO (Children ≥12 yr and 7.5–<15 kg): Oral pellets: 120 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease. Concurrent use with cyclosporine: Oral pellets: 60 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease.
PO (Children ≥12 yr and 6–<7.5 kg): Oral pellets: 80 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease. Concurrent use with cyclosporine: Oral pellets: 40 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease.
PO (Children 6 mo–<12 yr and ≥30 kg): Tablets or oral pellets: 480 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease. Concurrent use with cyclosporine: Tablets or oral pellets: 240 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease.
PO (Children 6 mo–<12 yr and 15–<30 kg): Tablets or oral pellets: 240 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease. Concurrent use with cyclosporine: Oral pellets: 120 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease.
PO (Children 6 mo–<12 yr and 7.5–<15 kg): Oral pellets: 120 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease. Concurrent use with cyclosporine: Oral pellets: 60 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease.
PO (Children 6 mo–<12 yr and 6–<7.5 kg): Oral pellets: 80 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease. Concurrent use with cyclosporine: Oral pellets: 40 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease.
IV (Children ≥12 yr and 15–<30 kg): 120 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease. Concurrent use with cyclosporine: 120 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease.
IV (Children ≥12 yr and 7.5–<15 kg): 60 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease. Concurrent use with cyclosporine: 60 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease.
IV (Children ≥12 yr and 6–<7.5 kg): 40 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease. Concurrent use with cyclosporine: 40 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease.
IV (Children 6 mo–<12 yr and ≥30 kg): 480 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease. Concurrent use with cyclosporine: 240 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease.
IV (Children 6 mo–<12 yr and 15–<30 kg): 120 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease. Concurrent use with cyclosporine: 120 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease.
IV (Children 6 mo–<12 yr and 7.5–<15 kg): 60 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease. Concurrent use with cyclosporine: 60 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease.
IV (Children 6 mo–<12 yr and 6–<7.5 kg): 40 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease. Concurrent use with cyclosporine: 40 mg once daily started between Day 0 and Day 28 post-transplantation and continued through Day 100 post-transplantation. May be continued through Day 200 post-transplantation if the patient is at risk for late CMV infection and disease.

Kidney Transplant

IV PO (Adults and Children ≥12 yr and ≥40 kg): 480 mg once daily started between Day 0 and Day 7 post-transplantation and continued through Day 200 post-transplantation. Concurrent use with cyclosporine: 240 mg once daily started between Day 0 and Day 7 post-transplantation and continued through Day 200 post-transplantation.

(Generic available)

Tablets: 240 mg; 480 mg
Oral pellets: 20 mg/pkt; 120 mg/pkt
Solution for injection: 20 mg/mL

Monitor for signs and symptoms of CMV reactivation (fatigue, fever, sore throat, muscle aches) when letermovir therapy completed.

IV administration is only used when patient unable to take oral dose and should not exceed 4 wk when possible.
IV and PO doses are interchangeable for adults and children >12 yr. Dose adjustments may be needed for children <12 yr when switching between formulations.
PO: Administer once daily without regard to food. DNC: Swallow tablets and oral pellets whole; do not crush, break, or chew. Oral pellets: Mix with 1–3 teaspoons of soft, room temperature food. Administer within 10 min of mixing. For administration via nasogastric (NG) or gastric (G-) tube, pour pellets into medicine cup with room temperature water (volume according to dose). For 120–480 mg dose, mix with 15 mL water for initial administration and rinse; administer through ≥ 8 French NG tube or any size G-tube. For 40–80 mg dose, mix with 3 mL water for initial administration and 2 mL water for rinse; administer through 5 French polyurethane or any ≥6 French NG tube, or any 12 French G-tube. Wait 10 min. Do not shake or swirl. Administer entire mixture within 2 hr. Add room temperature water to rinse medicine cup with appropriate volume, stir with syringe and administer entire rinse volume.

IV Administration:

Instruct patient to take letermovir as directed for full course of therapy. Take missed doses as soon as remembered on day of dose; do not take more than one dose/day. If remembered next day, skip previous dose and resume schedule; do not double doses.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking other Rx, OTC, or herbal products.
Rep: Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected or if breastfeeding.

Prevention of CMV infection.

Prevymis

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